Composition for promoting hair growth containing novel pantetheine derivative

ABSTRACT

Provided is a composition for promoting hair growth, containing, as an active ingredient, a new compound represented by the following formula 1 or a salt thereof, which exhibits an excellent effect of promoting the growth of dermal papilla cells to thereby exhibit the effect of promoting hair growth: 
     
       
         
         
             
             
         
       
     
     wherein R is any one selected from the group consisting of 2-methylbutyryl, 3-methylbutyryl, cinnamoyl, 4-pentenoyl, 10-undecenoyl, isobutyl formate, 2,4-dihydroxybenzoyl, geranyl, farnesyl, acryloyl, propanone, 2-pentanone, 1-(4-hydroxyphenyl)ethanone, 1-(2,4-dihydroxyphenyl)ethanone, pentanoic acid, 2-hydroxypropanoic acid, 2-phenylacetic acid, 2-(4-(propanoyl)phenyl)acetic acid, 4-methylbenzoic acid, 4-(4-phenyl)-4-oxobutanoic acid, 2-oxoethyl acetyl, 2-phenoxyacetyl, 2-(benzyloxy)acetyl, 4-methoxybenzoyl, 3,5-dimethylphenol, 6-methoxybenzene-1,4-diol, propenylbenzene, and 4-hydroxycoumarin.

BACKGROUND 1. Technical Field

The present invention relates to a composition for promoting hairgrowth, and more particularly to a composition for promoting hairgrowth, which contains a new pantetheine derivative that exhibits anexcellent effect of promoting the growth of dermal papilla cells tothereby promote hair growth.

2. Description of the Related Art

The known causes of hair loss include excessive male hormone production,excessive sebum secretion, scalp function deterioration caused byperoxides, bacteria, etc., genetic factors, aging, stress, and the like.In addition, the hair loss population is gradually increasing due toincreased social stress, environmental pollution, westernized eatinghabits such as the consumption of instant foods, frequent permanentwaves and hair color changes, etc.

The hair cycle can be divided into four separate stages: anagen wherehair grows; catagen where hair growth stops and the hair bulb shrinks;telogen where the dermal papilla stops its activity and hair remains onthe scalp; and exogen where the dermal papilla initiates its activity orproduces new hair to shed old hair.

The anagen stage (2-7 years) is a stage where hair grows. It issubdivided into two stages: a hair production stage where hair extendsfrom the hair bulb to the hair follicle; and a stage where hard keratinis produced in the hair follicle. Hair continues to grow until thecatagen stage.

The catagen stage (2-3 weeks) following the anagen stage is a stagewhere the metabolism of hair becomes slower while the shape of hair ismaintained. In this step, keratin is not produced. The hair in thecatagen stage occupies 1% of the total number of hairs. In this stage,the hair bulb shrinks to be divided into hair papillae, which aresurrounded by hair follicles and move upward, and cell division isarrested.

The telogen stage (3 months) is a stage where the hair papilla and thehair follicle gradually contracts and where the hair root is pushedupward and falls out. This stage where hair falls out continues for 3-4months until the next anagen stage is started.

Normal persons have a relatively large number of anagen-stage hairs,whereas persons with alopecia have a relatively large number oftelogen-stage hairs, and thus have visible hair loss. As hair lossprogresses, the period of the anagen stage becomes shorter, and for thisreason, hair gradually becomes thinner. Therefore, for the treatment ofhair loss, it is important to facilitate telogen-stage hair follicles toenter the anagen stage and to extend the shortened anagen stage.

Male pattern alopecia (androgenetic alopecia) is caused by the malehormone testosterone. If testosterone is converted to the highly activehormone dihydrotestosterone (DHT) by the enzyme 5α-reductase, thehormone dihydrotestosterone will act on hair follicles to induceanagen-stage hair follicles to enter the catagen stage, thereby causinghair loss. For this reason, for the treatment of androgenetic alopecia,methods for inhibiting DHT production caused by 5α-reductase have beenmainly used.

Female pattern alopecia is caused mainly by a decrease in estrogen levelafter the menopause. As a therapeutic agent against female patternalopecia, minoxidil or estrogen has been mainly used.

Alopecia areata is caused by autoimmune diseases, mental stress, orgenetic factors. The causes of alopecia areata fundamentally differ fromthose of androgenetic alopecia, and a method for treating alopeciaareata also differs from a method for treating androgenetic alopecia.Thus, for the treatment of alopecia areata, a method of applyingminoxidil to a hair loss area or artificial stimulation in a hair lossarea has been used.

However, agents such as minoxidil or trichosaccharides, known to date tohave effects on hair loss prevention and hair growth promotion, have nodistinct effect and cause side-effects such as induction of skinirritation. Thus, there is an urgent need to develop compositions havingdemonstrated safety and desired effects.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a hair growthstimulant, which is capable of promoting the proliferation of dermalpapilla cells to thereby prevent, alleviate or treat hair loss andexhibit excellent effects on hair growth or the like, and a cosmetic orpharmaceutical composition for promoting hair growth, which contains thehair growth stimulant.

To accomplish the above object, the present invention provides acomposition for promoting hair growth, containing, as an activeingredient, a compound represented by the following formula 1 or a saltthereof:

wherein R is any one selected from the group consisting of2-methylbutyryl, 3-methylbutyryl, cinnamoyl, 4-pentenoyl, 10-undecenoyl,isobutyl formate, 2,4-dihydroxybenzoyl, geranyl, farnesyl, acryloyl,propanone, 2-pentanone, 1-(4-hydroxyphenyl)ethanone,1-(2,4-dihydroxyphenyl)ethanone, pentanoic acid, 2-hydroxypropanoicacid, 2-phenylacetic acid, 2-(4-(propanoyl)phenyl)acetic acid,4-methylbenzoic acid, 4-(4-phenyl)-4-oxobutanoic acid, 2-oxoethylacetyl, 2-phenoxyacetyl, 2-(benzyloxy)acetyl, 4-methoxybenzoyl,3,5-dimethylphenol, 6-methoxybenzene-1,4-diol, propenylbenzene, and4-hydroxycoumarin.

In the composition for promoting hair growth according to the presentinvention, the compound represented by formula 1 is preferably any oneselected from the group consisting of 2-methylbutyryl-D-pantetheine,3-methylbutyryl-D-pantetheine, cinnamoyl-D-pantetheine,4-pentenoyl-D-pantetheine, 10-undecenoyl-D-pantetheine, isobutylformate-D-pantetheine, 2,4-dihydroxybenzoyl-D-pantetheine, andgeranyl-D-pantetheine.

In the composition for promoting hair growth according to the presentinvention, the compound represented by formula 1 exhibits the effect ofpromoting the growth of dermal papilla cells.

In the composition for promoting hair growth according to the presentinvention, the compound represented by formula 1 may be prepared usingD-pantethine as a starting material.

The composition for promoting hair growth according to the presentinvention may be a cosmetic composition for preventing hair loss andpromoting hair growth.

In the composition for promoting hair growth according to the presentinvention, the cosmetic composition preferably has any one formationselected from the group consisting of hair tonics, hair conditioners,hair essence, hair lotion, hair nourishing lotion, hair shampoo, hairrinse, hair treatments, hair cream, hair nourishing cream, hairmoisturizer cream, hair massage cream, hair wax, hair aerosols, hairpacks, hair nourishing pack, hair soap, hair cleansing foam, hair oil,hair drying preparations, hair preservation treatments, hair colorants,hair weaving preparations, color-removing preparations for hair, hairgel, hair glazes, hair dressingers, hair lacquers, hair moisturizers,hair mousse, and hair sprays.

The composition for promoting hair growth according to the presentinvention may be a pharmaceutical composition for preventing hair lossand promoting hair growth.

In the composition for promoting hair growth according to the presentinvention, the pharmaceutical composition preferably has any oneformation selected from the group consisting of ointments, pastes, gels,jellies, serums, aerosol sprays, non-aerosol sprays, foams, creams,lotions, solutions, and suspensions.

The hair growth stimulant according to the present invention exhibitsthe effect of promoting the proliferation of human dermal papilla cellsto thereby prevent hair loss and promote hair growth. Thus, the hairgrowth stimulant may be effectively used as an active ingredient incosmetic or pharmaceutical compositions for preventing hair loss andpromoting hair growth.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects, features and advantages of the presentinvention will be more clearly understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 shows a process of isolating new compounds (S1 and S2) for hairloss prevention and hair growth promotion from a culture broth of a102CH635-3 strain;

FIG. 2 shows a method of synthesizing new D-pantetheine derivativesaccording to the present invention; and

FIG. 3 shows the effects of new D-pantetheine derivatives according tothe present invention on the promotion of proliferation of dermalpapilla cells.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention will be described in detail.

The development and growth of hair and the hair cycle are controlled byhair papilla which is a tissue derived from the mesoderm of the hairfollicle base. It is known that the hair papilla interacts with hairmatrix cells and stimulates these cells to differentiate into severaltypes of cells that form hair follicles and hairs.

Hair follicles undergo repeated hair cycles, each consisting of anagenphase-catagen phase-telogen phase, and hair grows and falls out duringeach cell cycle. This cell cycle process is controlled by theinteractions between mesodermal and ectodermal cells, and dermal papillacells play a key role in this control. Mesodermal (dermal papilla) cellsinduce the production of hair in the anagen phase, and then secrete asubstance that stimulates the growth of hair. The catagen phase beginsin response to a change in dermal papilla cells, and as hair folliclesdegenerate, hair papilla moves upward and is placed immediately belowthe hair bulge in which hair stem cells exist. Following the telogenphase, the anagen phase begins in which hair stem cells divide by thesignal of dermal papilla cells to form new hair follicles.

According to the literature, the size and volume of dermal papillae inalopecia patients are significantly smaller than those in normalpersons. The number of dermal papillae increases in the anagen phase ofthe hair cycle, and the volume thereof is dependent on the number ofcells forming these dermal papillae. Furthermore, the volume anddivision of the epithelial tissue of the hair bulb are also dependent onthe volume of dermal papillae.

When a new anagen phase begins following the telogen stage, signalssimilar to those in the exogen stage act. It was reported that, in theinitial stage of the anagen stage, the signal of Wnt protein in theepithelial cells of the hair bulge adjacent to dermal papilla cells isvery strong, and Wnt/β-catenin signals or the like play an importantrole.

It is reported that the Wnt/β-catenin signaling system promotes theformation of hair follicles (“WNT signals are required for theinitiation of hair follicle development.” Andl T, et al. (2002) DevCell. 2: 643-653), and plays an important role in maintaining andactivating genes that are expressed during the anagen stage of the haircycle (“Wnt signaling maintains the hair-inducing activity of the dermalpapilla.” Kishimoto J, et al. (2000) Genes Dev 14: 1181-1185), andpromote differentiation from stem cells to keratinocytes (“β-catenincontrols hair follicle morphogenesis and stem cell differentiation inthe skin.” Huelsken J, et al. (2001) Cell 105: 533-545).

The present inventors have found that a composition containing, as anactive ingredient, a compound represented by the following formula 1 ora salt thereof, promotes the proliferation of dermal papilla cells tothereby increase the gene expression level of dermal papilla cellsrelated to hair loss prevention or hair growth promotion, therebycompleting the present invention:

wherein R is any one selected from the group consisting of2-methylbutyryl, 3-methylbutyryl, cinnamoyl, 4-pentenoyl, 10-undecenoyl,isobutyl formate, 2,4-dihydroxybenzoyl, geranyl, farnesyl, acryloyl,propanone, 2-pentanone, 1-(4-hydroxyphenyl)ethanone,1-(2,4-dihydroxyphenyl)ethanone, pentanoic acid, 2-hydroxypropanoicacid, 2-phenylacetic acid, 2-(4-(propanoyl)phenyl)acetic acid,4-methylbenzoic acid, 4-(4-phenyl)-4-oxobutanoic acid, 2-oxoethylacetyl, 2-phenoxyacetyl, 2-(benzyloxy)acetyl, 4-methoxybenzoyl,3,5-dimethylphenol, 6-methoxybenzene-1,4-diol, propenylbenzene, and4-hydroxycoumarin.

Preferably, the compound represented by formula 1 is any one selectedfrom the group consisting of 2-methylbutyryl-D-pantetheine,3-methylbutyryl-D-pantetheine, cinnamoyl-D-pantetheine,4-pentenoyl-D-pantetheine, 10-undecenoyl-D-pantetheine, isobutylformate-D-pantetheine, 2,4-dihydroxybenzoyl-D-pantetheine, andgeranyl-D-pantetheine.

It is to be understood that the compound of formula 1, which is used inthe present invention, may be provided not only as a free compound, butalso as a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable solvate thereof, a pharmaceutically acceptable polymorphthereof, or a pharmaceutically acceptable prodrug thereof. In addition,the active ingredient may be used alone or in combination with one ormore other pharmacologically active compounds.

A salt of the compound of formula 1, which is used as an activeingredient in the composition for promoting hair growth is notspecifically limited, as long as it may be used in medical or cosmeticpreparations. The salt may include an inorganic salt or an organic salt,and may be an acidic salt or an alkaline salt.

The composition according to the present invention may further containone or more other drugs or additives for the prevention or treatment ofhair loss or the promotion of hair growth. The other drugs or additivesinclude, but are not limited to, retinoic acid, minoxidil, finasteride,zinc peptides, zinc oxide, biotin, genistein, onion extracts, pumpkinseed oil, Emu oil, green tea extracts, Willow bark extracts, and thelike.

The composition for promoting hair growth according to the presentinvention may contain, based on the total amount of the composition,about 0.01-25 wt % of the compound of formula 1, and the content of thecompound of formula 1 in the composition may vary depending on the kindof compound of formula 1.

Where the composition for promoting hair growth according to the presentinvention is used as a pharmaceutical composition, may be appliedtopically to a portion in need of the prevention or treatment of hairloss or the promotion of hair growth, once or twice a day. When thecontent of the active ingredient in the composition is 1 wt %, theamount applied per day may be about 0.5-3 mg/cm² (skin surface area),and may vary depending on the area of a portion to which the activeingredient is to be applied. The amount and frequency of thisapplication may be suitably determined depending on the patient's ageand sex and the severity of hair loss.

A pharmaceutical composition containing the compound of formula 1 or asalt thereof may further contain a suitable carrier, excipient and/ordiluent, which is generally used in the preparation of pharmaceuticalcompositions.

The active ingredient of the composition of the present invention may beformulated with excipients, such as fillers, extenders, binders, wettingagents, disintegrants, surfactants or the like, or diluents, which arecommonly used. The composition of the present invention may furthercomprise an anti-coagulant, a lubricant, fragrance, an emulsifier, apreservative or the like, and may be formulated using a method wellknown in the art so as to provide quick, sustained or delayed release ofthe active ingredient after administration to mammals.

The pharmaceutical composition according to the present invention may beprepared as a conventional pharmaceutical formulation known in the fieldto which the present invention pertains. Preferably, it may be preparedas a formulation for transdermal administration or a skin externalpreparation for topical application.

Specifically, the composition of the present invention may be preparedas any formulations for skin application, for example, ointments,pastes, gels, jellies, serums, aerosol sprays, non-aerosol sprays,foams, creams, lotions, solutions, or suspensions.

A functional cosmetic composition containing, as an active ingredient,the hair growth stimulant of the present invention, may be prepared asany formulation for skin application. More specifically, the functionalcosmetic composition may be prepared as a formulation selected fromamong hair tonic, hair conditioner, hair essence, hair lotion, hairnourishing lotion, hair shampoo, hair rinse, hair treatment, hair cream,hair nourishing cream, hair moisturizer cream, hair massage cream, hairwax, hair aerosol, hair pack, hair nourishing pack, hair soap, haircleansing foam, hair oil, hair drying preparations, hair preservationtreatments, hair colorants, hair weaving preparations, color-removingpreparations for hair, hair gel, hair glazes, hair dressingers, hairlacquers, hair moisturizers, hair mousse, and hair sprays. In addition,it may be formulated in the form of skin contact materials such ascosmetic products, detergents or fibers.

In a cosmetic composition having each formulation according to thepresent invention, components other than the component of formula 1 or asalt thereof may be suitably selected and added by a person skilled inthe art within a range that does not impair the purpose and effect ofthe present invention. Examples of components that may be added to thecosmetic composition of the present invention include oil and fatcomponents, skin moisturizers, emollient agents, surfactants, organic orinorganic pigments, organic powder, UV-absorbing agents, preservatives,sterilizers, antioxidants, plant extracts, pH adjusting agents,alcohols, pigments, fragrance, blood circulation promoters,antiperspirants purified water, and the like.

Hereinafter, the present invention will be described in further detailwith reference to examples. However, it will be obvious to those skilledin the art that these examples are for illustrative purposes only andvarious changes and modifications are possible departing from the scopeand technical spirit of the present invention as disclosed in theappended claims.

1. Isolation and Identification of Bacillus sp. 102CH635-3 Strain

Microorganisms were isolated from marine sediment collected from thevicinity of the Chuuk Lagoon, Micronesia, in February 2010. 1 g of themarine sediment was heat-treated at 60° C. for 20 minutes, and thenstreaked on a BN agar plate. The microorganisms were cultured at 28° C.for 7 days while being observed, and an orange single colony of a102CH635-3 strain growing while spreading flatly was isolated. The102CH635-3 strain was preserved in 40% glycerol at −70° C.

For 16S rRNA sequencing of 102CH635-3, genomic DNA was amplified by PCRusing 16S rRNA primers (27F 5′(AGA GTT TGA TCM TGG CTC AG)3′ and 1492R5′(TAC GGY TAC CTT GTT ACG ACT T)3′). Specifically, a mixture of 20 ngof genomic DNA and 30 μl of EF-Taq (SolGent, Korea) reaction solutionwas subjected to PCR for 35 cycles. The PCR reaction was performed underthe following conditions: 35 cycles, each consisting of denaturation at95° C. for 1 min, primer annealing at 55° C. for 1 min, and chainextension at 72° C. for 1 min; followed by final chain extension at 72°C. for 10 minutes. A nucleotide sequence having a length of 1,380 bp ormore was obtained from the amplified DNA, and analyzed using an ABIprism 3730XL DNA analyzer (Applied Biosystems, Foster City, Calif.). Thehomology of the nucleotide sequence of the obtained marinemicroorganisms to those of strains deposited in the NCBI was analyzed byBlast search. As a result, the 102CH635-3 strain showed a sequencehomology of 99% to Bacillus subtilis and a sequence homology of 99% toBacillus amyloliquefaciens, and thus it was identified to be Bacillussp.

2. Establishment of Culture Conditions

A single colony of Bacillus sp. 102CH635-3 was inoculated into a flaskcontaining 50 ml of BN broth and was cultured at 28° C. for 7 days. Theculture broth was extracted with ethyl acetate and concentrated underreduced pressure to obtain a crude extract. The analysis of ¹H NMR datafor the crude extract indicated that the strain produced an interestingsubstance. Thus, the strain was selected as a useful strain forisolation of an active compound. Prior to mass culture of the strain, anexperiment for establishing optimal culture conditions under which anactive compound is produced was performed. As shown in Table 1 below,the BN medium from which the strain was isolated, and an SWNB mediumprepared by adding sea salt to an NB medium that is generally used forBacillus sp., were used.

TABLE 1 Composition of the culture media BN SWNB Components g/LD-glucose 10 — Tryptone 2 — Peptone — 5 Yeast extract 1 — Beef extract 13 Glucose 5 — Temperature (° C.) 28 28 Shaking speed (rpm) 140 140 Seasalt 32 32 pH 7.0 7.0 Culture duration 7 7 (days)

The 102CH635-3 strain was inoculated into 200 mL of each of brothshaving different medium compositions, after which it was cultured at 28°C. for 7 days, and then extracted with ethyl acetate and concentratedunder reduced pressure, thereby obtaining crude extracts. The ¹H NMRdata of the culture crude extracts obtained using the different mediumcompositions were analyzed. As a result, it could be seen that the useof the SWNB medium was effective for production of a useful compound.Thus, the SWNB medium was used as an optimal culture medium for massculture.

3. Mass Culture, and Isolation and Structural Determination of NewCompounds (S1 and S2) for Hair Loss Prevention/Hair Growth Promotion

A single colony of the Bacillus sp. 102CH635-3 strain was inoculated andseed-cultured at 28° C. and 120 rpm for 7 days. For mass culture, theseed strain was inoculated into a large-scale fermenter containing 30liters of SWNB medium and was cultured at 28° C. for 13 days. 30 litersof the resulting culture broth was centrifuged by a continuouscentrifuge, and the culture filtrate was extracted twice with the sameamount of ethyl acetate, and the mycelium was extracted twice withmethanol. The extract was concentrated by a vacuum evaporator to obtaina crude extract which was then stored at −20° C. until use as a samplefor isolation.

The ethyl acetate extract of the culture filtrate was fractionated byreverse-phase chromatography. As an elution solvent, a water/methanolmixture was used, and the ethyl acetate extract was fractionated into 5fractions (from a 20% methanol fraction to a 100% methanol fraction).The 60% methanol fraction was concentrated under reduced pressure,dried, and then recovered. This fraction was purified by C18reversed-phase HPLC (column: YMC-ODS-A, 5 μm, 10×250 mm; solvent: 45%MeOH; elution rate: 1.5 ml/min; RI detector) to isolate two singlecompounds. The finally isolated new compounds were2-methylbutyryl-D-pantetheine (S1; 0.5 mg) and3-methylbutyryl-D-pantetheine (S2; 1.9 mg) (see FIG. 1).

Structural elucidation by analysis of spectrometric data such as 1D NMR,2D NMR and HR-ESIMS indicated that S1 and S2 are new pantetheinederivatives. S1 showed a peak at m/z 385.1778 [M+Na]⁺ in HR-ESIMS andwas determined to have a molecular formula of C₁₆H₃₀N₂O₅S. The ¹H NMRspectrum of S1 showed that S1 has 4 methyl groups and 6 methylenegroups. The COSY spectrum of S1 showed the couplings of four methylenegroups, H-5/H-6 and H-8/H-9, and the HMBC spectrum revealed a partialstructure of S1 by showing the correlations between the amide carbons,C-4 (δ 176.2) and C-7 (δ 174.0), and the neighboring hydrogen atoms. Inaddition, comparison with that reported in the literature indicated thatS1 has a partial structure of pantetheine. Furthermore, the HMBCspectrum of S1 showed HMBC correlations between the carbonyl carbon atC-10 (δ 205.0) and H-9 (δ 3.00), H-12 (δ 1.48, 1.71) and H-14(δ 1.15),indicating that S1 is a new compound having a structure in which a2-methylbutyl group is attached to pantetheine. Moreover, in order todetermine the stereochemistry of C-3, the [α]_(D) value of S1 wascompared with that of D-pantetheine reported in the literature, and as aresult, it was determined that S1 and D-pantetheine have similar [α]_(D)values of +12.2 (c 3.45, H₂O) and +23.7 (c 0.5, H₂O), respectively.Thus, S1 was determined to be 2-methylbutyryl-D-pantetheine. TheHR-ESIMS of S2 showed that S2 has a molecular formula of C₁₆H₃₀N₂O₅S,suggesting that S2 has the same molecular weight and molecular formulaas those of S1. Analysis of various 1D and 2D NMR data, including ¹HNMR, ¹³C NMR and HMBC data, indicated that S2 has a structure verysimilar to that of S1. However, the COSY and HMBC spectra indicated thatS2 has a partial structure of a 3-methylbutyl group in which the methylgroup at δ 0.95 (d, J=5.0) is attached to a position different from thatin S1. Thus, the structure of S2 was determined to be3-methylbutyryl-D-pantetheine. In addition, the results of databasesearch indicated that S2 is a new compound that has not yet beenreported.

S1: [α]_(D) +23.7 (c 0.5, H₂O), ¹H NMR (CD₃OD, 500 MHz) 0.92 (s, CH₃),0.92 (s, CH₃), 0.92 (t, CH₃), 1.15 (d, J=5.0, CH₃), 1.48-1.71 (m, CH₂),2.41 (t, CH₂), 2.59 (m, CH), 3.00 (t, CH₂), 3.32 (t, CH₂), 3.38-3.46 (d,J=10.0, CH₂), 3.47 (m, CH₂), 3.89 (s, CH), ¹³C NMR (CD₃OD, 125 MHz)12.1, 17.8, 21.1, 21.5, 28.4, 29.0, 36.5, 36.6, 40.3, 40.5, 51.5, 70.5,77.4, 174.0, 176.2, 205.0, HR-ESIMS m/z 385.1778 [M+Na]⁺ (calculated forC₁₆H₃₀N₂O₅NaS, 385.1773).

S2: [α]_(D)+7.7 (c 0.5, H₂O), ¹H NMR (CD₃OD, 500 MHz) 0.92 (s, CH₃),0.92 (s, CH₃), 0.95 (d, J=5.0, CH₃), 0.95 (d, J=5.0, CH₃), 2.13 (m, CH),2.41 (t, CH₂), 2.46 (d, J=5.0, CH₂), 3.00 (t, CH₂), 3.32(t, CH₂),3.38-3.46 (d, J=10.0, CH₂), 3.47 (m, CH₂), 3.89 (s, CH), ¹³C NMR (CD₃OD,125 MHz) 21.1, 21.5, 22.7, 22.7, 27.8, 29.3, 36.5, 36.6, 40.3, 40.5,53.8, 70.5, 77.4, 174.0, 176.2, 200.2, HR-ESIMS m/z 385.1779 [M+Na]⁺(calculated for C₁₆H₃₀N₂O₅NaS, 385.1773).

TABLE 2 NMR data for S1 and S2 in CD₃OD S1 S2 δ_(H), mult. δ_(H), mult.No δ_(C) (J in Hz) HMBC δ_(C) (J in Hz) HMBC 1 70.5 3.38, C2, C3 70.53.38, C3 3.46 d 3.46 d (J = 10.0) (J = 10.0) 2 40.5 40.5 3 77.4 3.89, sC2, C4, 77.4 3.89, s C4 C15 4 176.2 176.2 5 36.5 3.47, m C4, C6, 36.53.47, m C4, C6, C7 C7 6 36.6 2.41, t C5, C7 36.6 2.41, t C5, C7 7 174.0174.0 8 40.3 3.32, t C7, C8 40.3 3.32, t C7, C9 9 29.0 3.00, t C8, C1029.3 3.00, t C8, C10 10 205.0 200.2 11 51.5 2.59, m C12 53.8 2.46, dC10, C12, (J = 5.0) C14 12 28.4 1.48, C10, C11 27.8 2.13, m 1.71, m 1312.1 0.92, t C11, C12 22.7 0.95, d C11, C12, (J = 5.0) C14 14 17.8 1.15,d C10, C11, 22.7 0.95, d C11, C12, (J = 5.0) C12 (J = 5.0) C13 15 21.10.92, s C2, C3, 21.1 0.92, s C2, C3, C16 C16 16 21.5 0.92, s C1, C1521.5 0.92, s C1, C2, C15

4. Synthesis of the New D-Pantetheine Compounds (S1 and S2) and TheirDerivatives

It is known that pantethine and pantetheine are the components of CoA(coenzyme A) and ACP (acyl carrier protein) and are involved in fattyacid and carbohydrate metabolisms after hydrolysis. It was reported thatthese compounds play a role in metabolic reactions, including fatty acidoxidation, amino acid degradation and cholesterol synthesis, and haveeffects against hyperlipidemia, hematological diseases, renal diseases,arteriolosclerosis, diabetes, and the like.Calcium-D-pantetheine-S-sulfonate is known to have whitening activity,moisturizing activity, melanin production inhibitory activity andanti-aging activity such as skin inflammation inhibitory activity, andthus has been used as an additive in famous cosmetic products in Koreaand other countries. Thus, in order to synthesize the new D-pantetheinecompounds isolated from the 102CH635-3 strain and their derivatives,studies on the synthesis of D-pantetheine compounds were conducted usingD-pantethine, thereby synthesizing not only the new natural compounds(S1 and S2), but also their derivatives.

Using commercially available D-pantethine (P2125, SIGMA), various newderivatives of D-pantetheine were synthesized according to the methodshown in FIG. 2. In a detailed synthetic method, dithiothreitol (DTT)and H₂O: MeOH (1:1, v/v) were added to D-pantethine, and the mixture wasallowed to react at 4° C. for 16 hours under N₂ atmosphere. After it wasconfirmed by TLC that D-pantethine disappeared, the reaction wasterminated, and the solvent was removed. Dry tetrahydrofuran (THF) andtriethylamine were added to the reaction product (pantetheine) fromwhich the solvent has been removed, and each of reagents having variousfunctional groups (R) was added thereto, after each of the mixtures wasallowed to react at 0° C. for 2 hours and at room temperature for 3hours.

Herein, R is one of 2-methylbutyryl, 3-methylbutyryl, cinnamoyl,4-pentenoyl, 10-undecenoyl, isobutyl formate, 2,4-dihydroxybenzoyl,geranyl, farnesyl, acryloyl, propanone, 2-pentanone,1-(4-hydroxyphenyl)ethanone, 1-(2,4-dihydroxyphenyl)ethanone,1-(2,4-dihydroxyphenyl)ethanone, pentanoic acid, 2-hydroxypropanoicacid, 2-phenylacetic acid, 2-(4-(propanoyl)phenyl)acetic acid,4-methylbenzoic acid, 4-(4-phenyl)-4-oxobutanoic acid, 2-oxoethylacetyl, 2-phenoxyacetyl, 2-(benzyloxy)acetyl, 4-methoxybenzoyl,3,5-dimethylphenol, 6-methoxybenzene-1,4-diol, propenylbenzene, and4-hydroxycoumarin.

After the reaction solvent was completely removed, the remainingmaterial was solvent-fractionated with H₂O:ethyl acetate (EtOAC) (1:1,v/v), and the ethyl acetate layer was recovered, treated with MgSO₄, andthen concentrated to obtain reaction products. It was confirmed byLR-APCIMS that the desired compounds were synthesized, and the productswere separated using HPLC. Purification was performed using C18reversed-phase HPLC (column: YMC-ODS-A, 5 μm, 10×250 mm; solvent: 60%MeOH; elution rate: 1.5 mL/min; RI detector) to separate various newderivatives.

Among the synthesized new derivatives, 2-methylbutyryl-D-pantetheine,3-methylbutyryl-D-pantetheine, cinnamoyl-D-pantetheine,4-pentenoyl-D-pantetheine, 10-undecenoyl-D-pantetheine, isobutylformate-D-pantetheine, 2,4-dihydroxybenzoyl-D-pantetheine andgeranyl-D-pantetheine were analyzed by ¹H NMR, ¹³C NMR and MSspectrometry to determine their structures. It is to be understood thatnew derivatives not described in this example can also be synthesizedaccording to the proposed synthetic method.

S1 (2-methylbutyryl-D-pantetheine): [α]_(D)+9.9 (c 1.0, H₂O), ¹H NMR(CD₃OD, 500 MHz) 0.92 (s, CH₃), 0.92 (s, CH₃), 0.92 (t, CH₃), 1.15 (d,J=5.0, CH₃), 1.48-1.71 (m, CH₂), 2.41 (t, CH₂), 2.59 (m, CH), 3.00 (t,CH₂), 3.32 (t, CH₂), 3.38-3.46 (d, J=10.0, CH₂), 3.47 (m, CH₂), 3.89 (s,CH), ¹³C NMR (CD₃OD, 125 MHz) 12.1, 17.8, 21.1, 21.5, 28.4, 29.0, 36.5,36.6, 40.3, 40.5, 51.5, 70.5, 77.4, 174.0, 176.2, 205.0, LR-APCIMS m/z360.99 [M−H]⁻, 362.87 [M+H]⁺, C₁₆H₃₀N₂O₅S.

S2 (3-methylbutyryl-D-pantetheine): [α]_(D)+5.9 (c 1.0, H₂O), ¹H NMR(CD₃OD, 500 MHz) 0.92 (s, CH₃), 0.92 (s, CH₃), 0.95 (d, J=5.0, CH₃),0.95 (d, J=5.0, CH₃), 2.13 (m, CH), 2.41 (t, CH₂), 2.46 (d, J=5.0, CH₂),3.00 (t, CH₂), 3.32 (t, CH₂), 3.38-3.46 (d, J=10.0, CH₂), 3.47 (m, CH₂),3.89 (s, CH), ¹³C NMR (CD₃OD, 125 MHz) 21.1, 21.5, 22.7, 22.7, 27.8,29.3, 36.5, 36.6, 40.3, 40.5, 53.8, 70.5, 77.4, 174.0, 176.2, 200.2,LR-APCIMS m/z 363.14 [M+H]⁺, C₁₆H₃₀N₂O₅S.

S3 (cinnamoyl-D-pantetheine): ¹H NMR (CD₃OD, 500 MHz) 0.92(s), 2.42(t),3.15(t), 3.35-3.51(m), 3.89(s), 6.86 (d, J=15.0), 7.41-7.42(m),7.62-7.66(m), ¹³C NMR (CD₃OD, 125 MHz) 21.1, 21.5, 29.4, 36.5, 36.6,40.3, 40.5, 50.0, 70.5, 77.4, 125.9, 129.8, 130.3, 132.0, 135.6, 142.3,176.2, 191.2, LR-APCIMS m/z 408.15 [M−H]⁻, 409.02 [M+H]⁺, C₂₀H₂₀N₂O₅S.

S4 (4-pentenoyl-D-pantetheine): ¹H NMR (CD₃OD, 500 MHz) 0.92(s),2.36-2.42(m), 2.68(t), 3.01(t), 3.32(t), 3.33-3.53(m), 3.89(s), 4.98(d,J=10.0), 5.05(d, J=15.0), 5.78-5.84(m), ¹³C NMR (CD₃OD, 125 MHz) 21.1,21.5, 29.3, 30.6, 36.4, 36.5, 40.2, 40.5, 44.1, 70.5, 77.4, 116.3,137.6, 174.0, 176.1, 199.9, LR-APCIMS m/z 360.90 [M+H]⁺, 721.25 [2M+H]⁺,C₁₆H₂₈N₂O₅S.

S5 (10-undecenoyl-D-pantetheine): ¹H NMR (CD₃OD, 500 MHz) 0.92(s),1.38(t), 1.64(m), 2.04(q), 2.41(t), 2.58(t), 3.00(t), 3.32-3.50(m),3.90(s), 4.90-4.92(dd), 4.96-5.00(m), 5.77-5.81(m) ¹³C NMR (CD₃OD, 125MHz) 21.1, 21.4, 26.8, 29.2, 30.1, 30.2, 30.2, 30.4, 30.5, 35.0, 36.4,36.5, 40.2, 40.5, 44.9, 70.5, 77.3, 114.9, 140.2, 173.9, 176.1, 200.7,LR-APCIMS m/z 443.10 [M−H]⁻, 415.10 [M+H]⁺, C₂₂H₄₀N₂O₅S.

S6 (isobutyl formate-D-pantetheine): ¹H NMR (CD₃OD, 500 MHz) 0.92(s),0.94 (d, J=10.0), 1,95(m), 2.42(t), 2.98(t), 3.38-3.50(m), 3.89(s), 4.01(d, J=5.0), ¹³C NMR (CD₃OD, 125 MHz) 19.3, 21.0, 21.5, 29.2, 31.3, 36.4,36.5, 40.4, 40.5, 70.5, 74.6, 77.3, 172.1, 174.0, 176.1, LR-APCIMS m/z376.95 [M−H]⁻, 378.90 [M+H]⁺, C₁₆H₃₀N₂O₆S.

S7 (2,4-dihydroxybenzoyl-D-pantetheine): ¹H NMR (CD₃OD, 500 MHz)0.91(s), 2.43(t), 2.72(t), 3.35-3.51(m), 3.85(s), 3.89(s), 6.27(d,J=2.5), 6.36 (dd, J=2.0, 10.0), 7.72 (d, J=10.0), ¹³C NMR (CD₃OD, 125MHz) 21.0, 21.5, 32.8, 36.5, 36.6, 37.3, 39.6, 40.5, 70.5, 77.4, 103.9,109.5, 112.7, 134.5, 166.9, 167.1, 174.0, 176.2, 201.0, LR-APCIMS m/z427.13 [M−H]⁻, 429.13 [M+H]⁺, C₁₉H₂₈N₂O₇S.

S8 (geranyl-D-pantetheine): ¹H NMR (CD₃OD, 500 MHz) 0.92(s), 1.61(s),1.67(s), 1.68(s), 2.05(t), 2.12(q), 2.42(t), 2.57(t), 3.18 (d, J=8.0),3.34-3.53(m), 3.89(s), 5.10(t), 5.23(t) ¹³C NMR (CD₃OD, 125 MHz) 16.3,17.9, 21.1, 21.5, 26.1, 27.7, 29.9, 31.3, 36.5, 36.6, 40.2, 40.5, 40.8,70.5, 77.4, 122.1, 125.3, 132.6, 140.1, 173.9, 176.2, LR-APCIMS m/z413.09 [M−H]⁻, 414.84 [M+H]⁺, C₂₂H₄₀N₂O₅S.

5. Effects of New D-Pantetheine Compounds on Hair Loss Prevention/HairGrowth Promotion

Dermal papilla cells play a key role in the production and growth ofhair, and compounds that promote the growth of dermal papilla cells areattracting attention as agents for preventing hair loss and promotinghair growth. In the present invention, in order to develop novelcompounds for hair loss prevention and hair growth promotion, theeffects of the new natural compounds and derivatives thereof on thepromotion of growth of dermal papilla cells were measured.

(1) Measurement of Viability of Dermal Papilla Cells

For cell culture, Dulbecco's Modified Eagle Medium (DMEM), fetal bovineserum (FBS), 0.25% trypsin-1 mM EDTA, and penicillin-streptomycin wereused, and dermal papilla cells were cultured at 37° C. in a humidified5% CO₂. The medium was replaced twice a week, and the cultured dermalpapilla cells were washed with PBS within 6-7 days. Next, the attachedcells were separated by 0.05% trypsin-0.02% EDTA, centrifuged, and thensubcultured for experiments. Specifically, 200 μl of dermal papillacells were dispensed into each well of a 96-well plate at a density of1×10⁴cells/well, and cultured under the conditions of 37° C. and 5% CO₂for 18 hours so as to be attached to each well. After 18 hours, themedium was removed, and 200 μl of samples was added to each well havingthe cells attached thereto, followed by culture for 24 hours. After themedium was removed, 100 μl of a solution of3-(4,5-dimethylthiazol)-2,5-diphenyltetrazoliumbromide(MTT), prepared bydissolving MTT in PBS at a concentration of 500 μg/ml, was added to thecultured cells, followed by culture for 4 hours under the sameconditions as described above. The formed formazan crystal was dissolvedin DMSO, and the absorbance at 570 nm was measured using an ELISAreader. The measured OD values ranging from 0.00 to 3.50 were used forthe experimental results. The sample for treatment of the cells was usedat concentrations of 0.5, 5 and 50 μM.

(2) Effects on Promotion of Growth of Dermal Papilla Cells

The results of the experiment for the new pantetheine compounds obtainedin the present invention (see FIG. 3 and Table 3) indicated that thepantetheine compounds showed excellent effects on the promotion ofgrowth of dermal papilla cells, and particularly, in the case of S1 andS6 among these compounds, the dermal papilla cell proliferation rateincreased up to 140%.

Although the effects of all the compounds represented by formula 1according to the present invention on the promotion of growth of dermalpapilla cells were not examined, it will be obvious that the compoundsthat were not examined show effects equal to those of compounds S1-S7,because these compounds have the same backbone structure as that ofcompounds S1-S7 and differ from compounds S1-S7 only in terms of thesubstituent groups.

TABLE 3 Effect of compounds S1-S7 on the growth of dermal papilla cellsConcentration (μM) Control 0.5 5 50 S1 (2-methylbutyryl- 100 113.31129.65 139.19 pantetheine) S2 (3-methylbutyryl- 100 121.04 114.65 121.28pantetheine) S3 (cinnamoyl-pantetheine) 100 119.77 122.38 133.33 S4(4-pentenoyl-pantetheine) 100 116.88 122.89 111.97 S5(10-undecenoyl-pantetheine) 100 111.24 93.01 101.62 S6 (isobutylformate- 100 130.57 112.94 135.95 pantetheine) S7 (2,4-dihydroxybenzoyl-100 95.73 97.32 93.12 pantetheine) minoxidil 100 146.66 146.52 140.29

As described above, the compounds according to the present inventionshowed activities of promoting the growth of dermal papilla cells, atlevels almost equal to that of minoxidil, and are new compounds thathave not yet been reported. These compounds of the present inventionhave a low molecular weight and are also easily synthesized. Thus, thepossibility for these compounds to be developed into cosmetic or medicalproducts for hair loss prevention and hair growth promotion is veryhigh.

Although the specific embodiments of the present invention have beendisclosed for illustrative purposes, those skilled in the art willappreciate that various modifications, additions and substitutions arepossible without departing from the scope and spirit of the invention asdisclosed in the accompanying claims.

1. A composition for promoting hair growth, containing, as an activeingredient, a compound represented by the following formula 1 or a saltthereof:

wherein R is any one selected from the group consisting of2-methylbutyryl, 3-methylbutyryl, 4 pentenoyl, 10-undecenoyl, isobutylformate, and 2,4-dihydroxybenzoyl.
 2. The composition of claim 1,wherein the compound represented by formula 1 is any one selected fromthe group consisting of 2-methylbutyryl-D-pantetheine,3-methylbutyryl-D-pantetheine, 4 pentenoyl-D-pantetheine,10-undecenoyl-D-pantetheine, isobutyl formate-D-pantetheine, and2,4-dihydroxybenzoyl-D-pantetheine.
 3. The composition of claim 1,wherein the compound represented by formula 1 exhibits an effect ofpromoting growth of dermal papilla cells.
 4. The composition of claim 1,wherein the compound represented by formula 1 is prepared usingD-pantethine as a starting material.
 5. The composition of claim 1,wherein the composition is a cosmetic composition for preventing hairloss and promoting hair growth.
 6. The composition of claim 5, whereinthe cosmetic composition has any one formation selected from the groupconsisting of hair tonics, hair conditioners, hair essence, hair lotion,hair nourishing lotion, hair shampoo, hair rinse, hair treatments, haircream, hair nourishing cream, hair moisturizer cream, hair massagecream, hair wax, hair aerosols, hair packs, hair nourishing pack, hairsoap, hair cleansing foam, hair oil, hair drying preparations, hairpreservation treatments, hair colorants, hair weaving preparations,color-removing preparations for hair, hair gel, hair glazes, hairdressingers, hair lacquers, hair moisturizers, hair mousse, and hairsprays.
 7. The composition of claim 1, wherein the composition is apharmaceutical composition for preventing hair loss and promoting hairgrowth.
 8. The composition of claim 7, wherein the pharmaceuticalcomposition has any one formation selected from the group consisting ofointments, pastes, gels, jellies, serums, aerosol sprays, non-aerosolsprays, foams, creams, lotions, solutions, and suspensions.